Abstract

Elevated levels of plasma homocysteine (Hcy) correlate with increased risk of cardiovascular and Alzheimer diseases. We studied the effect of elevated Hcy on the blood-brain barrier (BBB) to explore the possibility of a vascular link between the 2 diseases. On a hyperhomocysteinemic diet, cystathionine beta-synthase (Cbs)-heterozygous mice develop hyperhomocysteinemia. Intravital microscopy analysis of the mesenteric venules showed that leukocyte rolling velocity was markedly decreased and numbers of adherent cells were increased in the mutant mice. This was due at least in part to increased expression of P-selectin. BBB permeability was measured by Evans blue dye permeation and was found to be 25% greater in the Cbs(+/-) cortex compared with wild-type controls. Our study suggests an important toxic effect of elevated Hcy on brain microvessels and implicates Hcy in the disruption of the BBB.

Effect of hyperhomocysteinemia on leukocyte adhesion. (A) Plasma Hcy levels. n indicates number of mice; Diet, hyperhomocysteinemic diet. Data are presented as mean ± SEM. (B-C) Seven venules of 200 to 300 μm in diameter from 4 WT mice on chow, 7 venules from 4 WT, and 9 venules from 5 Cbs+/– on Diet were analyzed. (B) Leukocyte rolling velocity. Cumulative histogram of rolling velocities allows direct comparison of distribution among groups; number of leukocytes analyzed: WT (538), WT/Diet (339), and Cbs+/–/Diet (497). (C) Number of leukocytes adhering to the endothelium (> 20 seconds) over a 5-minute period. Each point represents a single venule. Leukocyte rolling velocities and number of adhering leukocytes were significantly different between Cbs+/–/Diet and WT, as well as Cbs+/–/Diet and WT/Diet (P < .05).